This application is a 371 of PCT/SE99/00732 filed May 3, 1999.
The present invention relates to compounds for use in the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum. 
Tuberculosis is still a major public health problem affecting nearly all parts of the world. Based on skin test reactivity it has been estimated that about one-third of the world""s population, i.e., 1.7 billion people, are infected with Mycobacterium tuberculosis. Despite the availability of effective chemotherapies, it is responsible for three million deaths and from eight to ten million new cases annually and thus remains the leading cause of death world-wide due to a single infectious agent: 26% of all preventable deaths, 7% of all deaths. According to the World Health Organisation, 450,000 deaths per year due to tuberculosis in developing countries occur in children under fifteen years of age, and the disease mostly affects the younger, more productive adults.
There are five front-line drugs known to be highly effective against M. tuberculosis and five second-line drugs that can be used when resistance to one or more of the front-line drugs is detected. The preferred mode of treatment for tuberculosis is the short course chemotherapy in which there are two phases. The first phase consists of a daily regimen for two months with isoniazid (300 mg), rifampicin (600 mg), pyrazinamide (3 g) and ethambutol (1.5 g). The second phase or the continuation phase consists of a daily regimen for the next four months with isoniazid and rifampicin. Although infection with drug-sensitive strains of M. tuberculosis can be effectively cured with the short course chemotherapy, the cure rate is very poor in most countries due to poor compliance which is reflective of the long duration of therapy.
The situation is further complicated by the rapid emergence of multi-drug resistant tuberculosis (MDR-TB) strains. For example, in certain populations, the incidence of resistance to isoniazid is as high as 26% and the resistance to rifampicin is about 15%. Prior to 1984, about 10% of tubercle bacilli isolated from patients in the United States were resistant to at least one single mycobacterial drug. By 1984, this figure had risen to 52%, of which over half (32%) were resistant to more than one drug (MDR-TB). Ten percent of the recorded MDR-TB cases have occurred in previously healthy people whose mortality ratexe2x80x9470 to 90%xe2x80x94has been nearly the same as that of immunosuppressed individuals with MDR-TB. The number of cases of MDR-TB has doubled since 1984 and in many of them the tubercle bacilli are resistant to both isoniazid and rifampicin. The median interval between diagnosis of MDR-TB and death is only four weeks and therefore MDR-TB demands a shorter response time between diagnosis and appropriate commencement of treatment. However, MDR-TB is difficult to treat as such since most patients do not respond very well to the second-line drugs and the cost of alternate treatment procedures, including hospitalisation and possibly surgery, increases the cost to as much as ten times the cost of traditional treatment.
Thus, there is an urgent medical need to identify new drugs with significant therapeutic activity against single- or multiple-drug resistant strains of M. tuberculosis and with pharmacokinetic properties that permit reduced dosing which will in turn encourage better compliance.
In accordance with the present invention, there is therefore provided the use of a compound of general formula 
wherein x is 0 or 1;
R1 represents a hydrogen atom, or a C1-C20 alkyl or myrtanyl group, or a phenyl or benzyl group optionally substituted in the aromatic ring by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl, or a group (CH2)yCONHxe2x80x94R5 where y is an integer from 1 to 6 and R5 represents a phenyl group optionally substituted by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl; and either
R2 represents a hydrogen atom or a C1-C6 alkyl group, or R2 together with R3 represents a carbon-carbon single bond provided that x is 0, or R2 together with R4 represents a group xe2x95x90CH2,
R3 represents a hydrogen atom or is linked to R2 as defined above, and
R4 represents a hydrogen atom or a C1-C6 alkyl group; or a C1-C10 alkylamino group optionally substituted by a di(C1-C6 alkyl)amino substituent group; or an anilino group optionally substituted in the aromatic ring by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl; or a group xe2x80x94SCH2CH2OH, xe2x80x94SCH2CH2NH2, xe2x80x94SCH2CH2(NH2)CO2H or xe2x80x94SCH2CH2NHCOxe2x80x94R6 where R6 represents a
C1-C10 alkyl or C3-C6 cycloalkyl group, or a phenyl group optionally substituted by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl,
C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl;
or R4 is linked to R2 as defined above;
or
R2, R3 and R4 together represent a phenyl group;
with the provisos that:
(i) R1, R2, R3 and R4 do not each simultaneously represent a hydrogen atom,
(ii) when x is 0, R1 represents a 4-fluorophenyl group and R4 represents a hydrogen atom, then R2 and R3 do not together represent a carbon-carbon single bond, and
(iii) when x is 0, R1 represents a 4-fluorophenyl group and R2 and R3 both represent a hydrogen atom, then R4 does not represent an anilino, 4-chloroanilino, 2,6-dichloroanilino, 3,4-dichloroanilino, 2,5-dichloroanilino, 3-chloro-4-fluoroanilino or 4-fluoroanilino group;
or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a mycobacterial disease, in particular tuberculosis.
In the context of the present specification, unless otherwise stated, an alkyl (substituent) group or an alkyl moiety in an alkoxy or alkoxycarbonyl substituent group may be linear or branched.
Preferably R1 in formula (I) represents a hydrogen atom, or a C1-C15, more preferably C1-C10, alkyl or myrtanyl group, or a phenyl or benzyl group optionally substituted in the aromatic ring by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl), C1-C4 alkoxy (e.g. methoxy, ethoxy, propoxy, or butoxy), C1-C4 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl, or a group (CH2)yCONHxe2x80x94R5 where y is an integer 1, 2, 3 or 4 and R5 represents a phenyl group optionally substituted by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl), C1-C4 alkoxy (e.g. methoxy, ethoxy, propoxy, or butoxy), C1-C4 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl.
The group R1 especially represents a hydrogen atom, or a C4-C10 alkyl (e.g. butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl) or myrtanyl group, or a phenyl group substituted by a piperidyl substituent group, or a group (CH2)yCONHxe2x80x94R5 where y is 1 or 2 and R5 represents a phenyl group substituted by a piperidyl substituent group.
Preferably R2 represents a hydrogen atom or a C1-C4 alkyl, particularly methyl, group, or R2 together with R3 represents a carbon-carbon single bond provided that x is 0, or R2 together with R4 represents a group =CH2.
R4 preferably represents a hydrogen atom or a C1 -C4 alkyl group (e.g. methyl, ethyl, propyl or butyl); or a C2-C10 alkylamino group optionally substituted by a di(C1-C6 alkyl)amino, especially di(C1-C4 alkyl)amino, substituent group; or an anilino group optionally substituted in the aromatic ring by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl), C1-C4 alkoxy (e.g. methoxy, ethoxy, propoxy, or butoxy), C1-C4 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl; or a group xe2x80x94SCH2CH2OH, xe2x80x94SCH2CH2NH2, xe2x80x94SCH2CH2(NH2)CO2H or xe2x80x94SCH2CH2NHCOxe2x80x94R6 where R6 represents a C5-C10 alkyl or C3-C6 cycloalkyl group, or a phenyl group optionally substituted by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl), C3-C6 alkoxy (e.g. propoxy, butoxy, pentoxy or hexyloxy), C1-C4 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl; or R4 is linked to R2 as defined above.
It is preferred that R4 represents a hydrogen atom, a methyl or ethyl group, a C2-C10 alkylamino group optionally substituted by a di(C2-C4 alkyl)amino substituent group, an anilino group substituted by a piperidyl substituent group, xe2x80x94SCH2CH2OH, xe2x80x94SCH2CH2NH2, xe2x80x94SCH2CH2(NH2)CO2H, xe2x80x94SCH2CH2NHCOxe2x80x94R6 where R6 represents a C7 alkyl, cyclopropyl, cyclopentyl or cyclohexyl group or a phenyl group substituted by a nitro, C1-C4 alkyl or C3-C6 alkoxy substituent group, or R4 is linked to R2 as defined above.
Particularly preferred compounds of formula (I) include:
1-Decylpyrrolidine-2,5-dione,
1-Nonylpiperidine-2,6-dione,
2-((6,6-Dimethylbicyclo[3,1,1]hept-2-yl)methyl)isoindole-1,3-dione,
1-((6,6-Dimethylbicyclo[3,1,1]hept-3-yl)methyl)-3-methyl-3-pyrroline-2,5-dione,
3-Methyl-1-nonyl-3-pyrroline-2,5-dione,
3-Methylene-1-nonylpyrrolidine-2,5-dione,
3-Methyl-1-octyl-3-pyrroline-2,5-dione,
3-Methylene-1-octylpyrrolidine-2,5-dione,
(4-(3-methyl-2,5-dioxo-3-pyrrolinyl)phenyl)piperidine,
1-Octyl-3-pyrroline-2,5-dione,
1-Decyl-3-pyrroline-2,5-dione,
1-Nonyl-3-pyrroline-2,5-dione,
1-Butyl-3-pyrroline-2,5-dione,
1-Hexyl-3-pyrroline-2,5-dione,
1-(4-Piperidylphenyl)-3-pyrroline-2,5-dione,
1-(Octyl-3-(octylamnino)-pyrrolidine-2,5-dione,
1-Decyl-3-(decylamino)pyrrolidine-2,5-dione,
3-(Octylamiino)-3-pyrrolidine-2,5-dione,
3-(Heptylamino)-1-nonyl pyrrolidine-2,5-dione,
1-Nonyl-3-(nonylamino)pyrrolidine-2,5-dione,
1-Nonyl-3-(octylamino)pyrrolidine-2,5-dione,
2-Arnino-3-(3-methyl-1-nonyl-2,5-dioxo-pyrrolidin-3-ylthio)propanoic acid,
2-Amnino-3-(3-methyl-1-octyl-2,5-dioxo-pyrrolidin-3-ylthio)propanoic acid,
2-Amino-3-(1-octyl-2,5-dioxo-pyrrolidin-3-ylthio)propanoic acid,
3-Methyl-1-octylpyrrolidine-2,5-dione,
3-Methyl-1-nonylpyrrolidine-2,5-dione,
2-(2,5-Dioxopyrrolidinyl)-N-(4-piperidylphenyl)ethanamiide,
2-(2,5-Dioxopyrrolidinyl)-N-(4-piperidylphenyl)propanacide,
3-Ethyl-1-nonylpyrrolidine-2,5-dione,
3-(2-Aminoethylthio)-1-nonylpyrrolidine-2,5-dione,
2-Ethyl-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)hexanamide,
Cyclopropyl-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
(4-Butylphenyl)-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
(4-Hexyloxyphenyl)-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
(4-Methylphenyl)-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
(4-(tert-Butyl)phenyl-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
Cyclopentyl-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide, ethane,
Cyclohexyl-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
(4-Nitrophenyl)-N-(2-(1-nonyl-2,5-dioxopyrrolidin-3-ylthio)ethyl)formamide,
3-((2-(Dibutylamino)ethyl)amino)-1-nonylpyrrolidine-2,5-dione,
3-((2-(Diethylamino)ethyl)amino)-1-nonylpyrrolidine-2,5-dione,
1-Nonyl-3-((4-piperidinylphenyl)amino)pyrrolidine-2,5-dione,
3-(Hydroxyethylthio)-3-methyl-1-nonylpyrrolidine-2,5-dione,
3-(2-Aminoethylthio)-3-methyl-1-nonylpyrrolidine-2,5-dione, and
3-Methyl-1-octyl-3-(octylamino)pyrrolidine-2,5-dione.
The compounds of formula (I) are known compounds or may be prepared using techniques conventional in the art. The compounds of formula (I) may, if desired, be converted to a pharmaceutically-acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of formula (I) are advantageous in that they possess bactericidal activity against mycobacteria, particularly pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. aviur and M. marinum. 
Accordingly, in another aspect, the invention provides a method of treating a patient suffering from, or at risk of, a mycobacterial disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as defined above.
The compounds of formula (I) and pharmaceutically-acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.10 to 70%w, of active ingredient, and, from 1 to 99.95%w, more preferably from 30 to 99.90%w, of a pharmaceutically-acceptable adjuvant, diluent or carrier, all percentages by weight being is based on total composition. The pharmaceutical composition may additionally contain another anti-tubercular agent and/or various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
The daily dosage of formula (I) compound administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound of formula (I) is administered at a daily dosage not exceeding 1 g, e.g. in the range from 10 to 50 mg/kg body weight.
The compounds of formula (I) may be administered systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions.
The present invention will now be further explained with reference to the following illustrative examples.